Pharmacovigilance of unlicensed cannabidiol in European countries.

Cannabidiol (CBD) is a multitarget agent possessing anti-inflammatory and antioxidant properties. Unlicensed CBD gained public favor for the care of general health and well-being as well as to get comfort from inflammatory complaints, pain, anxiety, mood, and sleep disorders. Safety profile of unlicensed CBD has been not sufficiently described. For this reason, suspected adverse reactions (SARs) to CBD unlicensed products were analyzed. Serious SARs to unlicensed CBD products in EudraVigilance, a system purchased by the European Medicines Agency, were analyzed for age, sex of the patient, adverse reactions, indication for use, and concomitant drugs. Serious SARs were 18.9% of all adverse events to unlicensed CBD; they were more frequent in men and adult people and, to a less extent, in children (3-11 years). About sex, in EudraVigilance serious Individual Cases Safety Reports of SARs to CBD in men are in the largest number (58.8%) with respect to women. Unlicensed CBD was used in the 38.8% of cases for treatment of epilepsy; more frequent adverse effects were: mental disorders, hepatic disorders, and aggravation of pre-existing epilepsy. Drugs or substances more frequently associated with SARs were the antiepileptics clobazam and valproic acid, followed by cannabis. Results suggest that precautions and appropriate surveillance of adverse effects should be taken when unlicensed CBD is used.

Efficacy and safety of the syrup "KalobaTUSS®" as a treatment for cough in children: a randomized, double blind, placebo-controlled clinical trial.

BACKGROUND: Acute cough in children often causes discomfort to children and parents, reducing their quality of life. Despite the extensive utilization of over-the-counter remedies for cough, the efficacy of most of these treatments in children has not been confirmed. METHODS: We conducted a randomized, double blind, placebo-controlled clinical trial of 106 children with acute cough to evaluate the efficacy and safety of KalobaTUSS®, a paediatric cough syrup based on acacia honey and on Malva sylvestris extract, Inula helenium extract, Plantago major extract, and Helichrysum stoechas extract by using a validated 6 points Likert scale. RESULTS: Children were orally treated with KalobaTUSS® or placebo for 8 days. Children receiving KalobaTUSS® showed an early and significant reduction in night-time and day-time cough scores measured using a specific scale and a shorter duration of cough than children treated with the placebo. CONCLUSIONS: KalobaTUSS® is well tolerated and produces positive effects by reducing the severity and shortening the duration of cough in children. TRIAL REGISTRATION: Clinicaltrials.gov no. NCT04073251 . Retrospectively registered.

A standardized extract of Opuntia ficus-indica (L.) Mill and Olea europaea L. improves gastrointestinal discomfort: A double-blinded randomized-controlled study.

Gastrointestinal discomfort (GD), which often includes gastroesophageal reflux disease (GERD), is a common disorder in healthy adults affecting 40% of the worldwide population. The symptoms related to GD can have a negative impact on the quality of life (QoL). Current treatments for GERD are associated with side effects. We conducted a randomized double-blind placebo-controlled trial to assess the effect of a standardized extract of Opuntia ficus-indica L. cladodes and Olea europaea L. leaves on the symptoms and QoL of healthy adults with GD. One hundred healthy participants with GD were enrolled in the study and divided into two groups: 60 participants taking verum (400 mg/day) and 40 taking the placebo for 8 weeks. The Gastrointestinal Quality of Life index (GIQLI) and GERD Symptom Assessment Scale (GSAS) questionnaires were administered at the beginning of the study and after 4 and 8 weeks. The group treated with verum experienced a statistically significant improvement of GIQLI and GSAS scores (p < .001). Moreover, the effect size measured revealed a clinical significance. A day-dependent improvement of symptoms was also observed. The standardized extract represents a fast, effective, and well-tolerated treatment for improving symptoms related to GD and GERD.

Safety of Medical Cannabis in Neuropathic Chronic Pain Management.

Products derived from the plant Cannabis sativa are widely appreciated for their analgesic properties and are employed for the treatment of chronic neuropathic pain. Only nabiximols, a product composed of two extracts containing similar percentages of the two cannabinoids cannabidiol and delta-9-tetrahydrocannabinol, is approved by regulatory authorities for neuropathic pain and spasticity due to multiple sclerosis in many European countries and Canada. It is also included in pharmacovigilance systems monitoring the occurrence of adverse drug reactions. However, it is not the same for the great variety of other cannabis preparations widely used for medical purposes. This creates a situation characterized by insufficient knowledge of the safety of cannabis preparations and the impossibility of establishing a correct risk-benefit profile for their medical use in the treatment of chronic neuropathic pain. With the aim to explore this issue more deeply, we collected data on adverse reactions from published clinical studies reporting the use of cannabis for neuropathic relief.

Alarmins in Osteoporosis, RAGE, IL-1, and IL-33 Pathways: A Literature Review.

Alarmins are endogenous mediators released by cells following insults or cell death to alert the host's innate immune system of a situation of danger or harm. Many of these, such as high-mobility group box-1 and 2 (HMGB1, HMGB2) and S100 (calgranulin proteins), act through RAGE (receptor for advanced glycation end products), whereas the IL-1 and IL-33 cytokines bind the IL-1 receptors type I and II, and the cellular receptor ST2, respectively. The alarmin family and their signal pathways share many similarities of cellular and tissue localization, functions, and involvement in various physiological processes and inflammatory diseases including osteoporosis. The aim of the review was to evaluate the role of alarmins in osteoporosis. A bibliographic search of the published scientific literature regarding the role of alarmins in osteoporosis was organized independently by two researchers in the following scientific databases: Pubmed, Scopus, and Web of Science. The keywords used were combined as follows: "alarmins and osteoporosis", "RAGE and osteoporosis", "HMGB1 and osteoporosis", "IL-1 and osteoporosis", "IL 33 and osteopororsis", "S100s protein and osteoporosis". The information was summarized and organized in the present review. We highlight the emerging roles of alarmins in various bone remodeling processes involved in the onset and development of osteoporosis, as well as their potential role as biomarkers of osteoporosis severity and progression. Findings of the research suggest a potential use of alarmins as pharmacological targets in future therapeutic strategies aimed at preventing bone loss and fragility fractures induced by aging and inflammatory diseases.

Prognostic relevance of oxidative stress measurement in chronic lymphocytic leukaemia.

OBJECTIVE: To evaluate the prognostic significance of oxidative stress (OS) and antioxidant defence status measurement in patients with chronic lymphocytic leukaemia (CLL). METHODS: d-ROMs test and BAP test were evaluated at diagnosis of 165 patients with CLL and correlated with clinical-biological features and prognosis. RESULTS: An increased oxidative damage (d-ROMs test) and a reduced antioxidant potential (BAP test) were found in CLL patients than normal controls (P<.0001). CLL patients with higher d-ROMs values had higher number of circulating white blood cells and lymphocytes, and higher values of ß2 -microglobulin. Higher d-ROMs values were found in female (P=.0003), in patients with unmutated IgVH (P=.04), unfavourable cytogenetics (P=.002) and more advanced clinical stage (P=.002). Higher BAP test values were found in patients expressing CD49d (P=.01) and with more advanced clinical stage (P=.004). At a median follow-up of 48 months, CLL patients with d-ROMs ≥418 CARR U were found to have a shorter time to first treatment (TFT) (P=.0002), and a reduced survival (P=.006) than others. CLL patients with BAP test values ≥2155 µmol/L had a shorter TFT (P=.008) and a shorter survival (P=.003). CONCLUSIONS: OS can affect CLL patients by concomitantly increasing reactive oxygen metabolites production and decreasing antioxidant defences.

Contact dermatitis as an adverse reaction to some topically used European herbal medicinal products - part 4: Solidago virgaurea-Vitis vinifera.

This review focuses on contact dermatitis as an adverse effect of a selection of topically used herbal medicinal products for which the European Medicines Agency has completed an evaluation up to the end of November 2013 and for which a Community herbal monograph - now (since 2014) called a 'European Union herbal monograph' - has been produced. The present part 4 addresses species from Solidago virgaurea L. to Vitis vinifera L.

Involvement of microRNAs in skin disorders: A literature review.

BACKGROUND: miRNAs are a class of noncoding RNA molecules that modulate gene expression after transcription. It is known that miRNAs are involved in various cellular processes of both normal and diseased skin. Recently, differential expressions of miRNAs have been reported and associated with several immunologic and inflammatory disorders, which indicate a common role in fundamental biologic processes. OBJECTIVE: To collect and review data from the literature on involvement of miRNA in inflammatory skin disorders. METHODS: A bibliographic search of scientific literature was carried out independently by two researchers in scientific data bases and search engines. The MeSH terms used were the following: "microRNAs" combined with "skin," "dermatitis," "urticaria," "eczema," "hypersensitivity." All research articles from inception until April 2016 were considered. RESULTS: A total of 11 research articles on the study of miRNAs in inflammatory skin disorders (atopic dermatitis, delayed-type hypersensitivity, eczema, toxic epidermal necrolysis) were identified. All the studies confirmed the main role of endogenous noncoding RNAs in diseases such as atopic dermatitis, allergic contact dermatitis, eczema, and toxic epidermal necrolysis. CONCLUSION: The miRNAs seem to influence regulatory mechanisms of inflammation in both inducing and contrasting acute and chronic skin inflammation. They also seem to be useful instruments in identifying and staging diseases such as dermatitis and other inflammatory skin diseases. Also, the potential application of miRNAs in genetic therapies demonstrated its efficacy on animal models.

Clinical Pharmacology of Citrus bergamia: A Systematic Review.

Citrus bergamia Risso et Poiteau ("Bergamot") originated from the Mediterranean ecoregion (southern Italy, Calabria). Bergamot essential oil (BEO) is used in perfumes, cosmetics, and for stress reduction. Juice from C. bergamia has been used for hyperlipidemia. We evaluated literature published on C. bergamia clinical applications. Clinical trials on C. bergamia not combined with other substances, published in English, were searched. We selected ten articles, six describing BEO effects on stress, three reporting effects of polyphenolic fraction of C. bergamia juice in hyperlipidemia and the last describing BEO effects in chronic psoriasis. Clinical studies were analyzed following Consolidated Standards of Reporting Trials for herbal therapy. Studies were conducted on small sample sizes and not have high quality level. Analysis indicates that BEO aromatherapy could be safe and useful to reduce stress symptoms. One study suggests its potential supportive role in ultraviolet B therapy against psoriasis. Supplementation with polyphenols from bergamot juice reduces plasma lipids and improves lipoprotein profile in moderate hyperlipidemia. Effectiveness and safety of C. bergamia cannot be definitively drawn because of publication bias and low quality level of the majority of studies. Further large-scale trials with rigorous design are required to define the role of C. bergamia in clinical practice. Copyright © 2016 John Wiley & Sons, Ltd.

Systematic review and meta-analysis of the risk of severe and life-threatening thromboembolism in cancer patients receiving anti-EGFR monoclonal antibodies (cetuximab or panitumumab).

Cancer-associated thromboembolism is a substantial problem in clinical practice. An increase in the level of fibrinopeptide A (a substance associated with hypercoagulable states) has been observed in humans exposed to fluorouracil. Anti-EGFR monoclonal antibodies cetuximab and panitumumab, which are now widely used in patients with metastatic colorectal cancer, could prolong the uncovering of endothelial structures resulting from flouorouracil or other co-administered agents, thus favouring several factors leading to thromboembolism. We performed a systematic review and meta-analysis of randomised, controlled trials assessing whether cancer patients receiving anti-EGFR monoclonal antibodies cetuximab and panitumumab are at increased risk of thromboembolic events. We searched electronic databases (Medline, Embase, Web of Science, Central) and reference lists. Phase II/III randomised, controlled trials comparing standard anti-cancer regimens with or without anti-EGFR monoclonal antibodies and reporting serious venous thromboembolic events were included in the analysis. Seventeen studies (12,870 patients) were considered for quantitative analysis. The relative risk (RR) for venous thromboembolism (18 comparisons) was 1.46 (95% CI 1.26 to 1.69); the RR of pulmonary embolism, on the basis of eight studies providing nine comparisons, was 1.55 (1.20 to 2.00). Cancer patients receiving anti-EGFR monoclonal antibodies-containing regimens are approximately 1.5 times more likely to experience venous or pulmonary embolism, compared to those treated with the same regimens without anti-EGFR monoclonal antibodies. Clinicians should consider patient's baseline thromboembolic risk when selecting regimens that include cetuximab or panitumumab. Potential non-reporting of these important adverse events remains a concern. PROSPERO registration number is CRD42014009165.

Lethal Anaphylactic Reaction to Intravenous Gelatin in the Course of Surgery.

Plasma volume expanders (PVEs) are widely used to increase circulating blood volume. Gelatins used as PVEs are heterogeneous mixtures of polypeptides, usually prepared by hydrolysis of bovine collagen containing large amounts of proline and hydroxyproline residues. It has been shown that gelatins can cause anaphylactic reactions. We describe the case of a 73-year-old man who during surgery for intestinal obstruction presented a lethal anaphylactic reaction after the administration of a PVE containing gelatin lysate. The reaction occurred 10 minutes after the start of plasma expander infusion. Then, patient became comatose, and he died without awakening after 76 days. Necroptic aspects and histologic evaluation suggested the occurrence of anaphylactic reaction. According to pharmacovigilance algorithm, the causality relationship between PVE administration and adverse reaction has been considered as probable. We described a new lethal adverse reaction caused by PVEs containing gelatin. It is currently considered a very rare event, but we believe that it represents an important signal suggesting for a critical surveillance comprising a complete evaluation of individual's allergic susceptibility.

Contact dermatitis as an adverse reaction to some topically used European herbal medicinal products - Part 3: Mentha × piperita - Solanum dulcamara.

This review focuses on contact dermatitis as an adverse effect of a selection of topically used herbal medicinal products for which the European Medicines Agency has completed an evaluation up to the end of November 2013 and for which a Community herbal monograph - now (since 2015)(†) called a European Union herbal monograph - has been produced. Part 3: Mentha × piperita L.-Solanum dulcamara L.

Association between urticaria and virus infections: A systematic review.

BACKGROUND: The association between urticaria and virus infections has rarely been reported in the literature. The lack of reported cases is probably due to the difficulty in establishing a cause-and-effect relationship. It is not possible to challenge the patient with an etiologic agent. OBJECTIVE: The purpose of this work was to perform a systematic review on the association between urticaria and virus infections. METHODS: This systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. We searched for articles from January 1, 2008, through May 2015, by using two key terms related to urticaria and virus diseases, "urticaria" and one key term related to virus infections, "virus disease," then "urticaria" and the name of each virus family, and of the most representative virus serotypes. RESULTS: We reported cases of patients affected either by acute or chronic urticaria with a concurrent virus infection. Previous other causes of urticaria had to be excluded. Herpesviridae infections and urticaria were the most frequently reported associations in children. However, hepatitis virus infections would appear to be the most-frequent cause of urticaria in adults. CONCLUSIONS: Data obtained indicated viral infection as a potential trigger and sometimes as the main etiologic agent in causing acute or chronic urticaria. In every case, urticarial manifestation cleared up after either healing or controlling of the viral infection. However, prospective studies and well-structured research is needed to better clarify the role of viruses in the pathogenesis of urticaria and their relative prevalence.

Fatal Anaphylactic Shock Ceftriaxone-Induced in a 4-Year-Old Child.

One of the most used cephalosporin in clinical practice is ceftriaxone. Anaphylaxis due to the administration of ceftriaxone is considered a rare event. Here, we report a case of fatal anaphylactic shock after the administration of ceftriaxone in a child who had tolerated the drug in past exposures. The allergic pathogenesis is sustained by the clinical data (short time between the inoculation of the drug and the onset of the symptoms; past exposure to the same molecule and probable sensitization) and the postmortem examination findings (polivisceral congestion and intense eosinophilia found in the histological examination).

Anti-Inflammatory Activity of Citrus bergamia Derivatives: Where Do We Stand?

Inflammatory diseases affect a large portion of the worldwide population, and chronic inflammation is a major risk factor for several dangerous pathologies. To limit the side effects of both synthetic and biological anti-inflammatory drugs, the use of herbal medicines, nutraceuticals and food supplements has increased tremendously as alternative and/or complementary medicine to treat several pathologies, including inflammation. During the last decades, the biological properties of Citrus bergamia (bergamot) derivatives have obtained important scientific achievements, and it has been suggested their use in a context of a multitarget pharmacological strategy. Here, we present an overview of the anti-inflammatory properties of bergamot extracts that could represent the scientific basis for develop novel and alternative strategies to improve health status and attenuate inflammatory conditions.

Neurodegenerative Diseases: Might Citrus Flavonoids Play a Protective Role?

Neurodegenerative diseases (ND) result from the gradual and progressive degeneration of the structure and function of the central nervous system or the peripheral nervous system or both. They are characterized by deterioration of neurons and/or myelin sheath, disruption of sensory information transmission and loss of movement control. There is no effective treatment for ND, and the drugs currently marketed are symptom-oriented, albeit with several side effects. Within the past decades, several natural remedies have gained attention as potential neuroprotective drugs. Moreover, an increasing number of studies have suggested that dietary intake of vegetables and fruits can prevent or delay the onset of ND. These properties are mainly due to the presence of polyphenols, an important group of phytochemicals that are abundantly present in fruits, vegetables, cereals and beverages. The main class of polyphenols is flavonoids, abundant in Citrus fruits. Our review is an overview on the scientific literature concerning the neuroprotective effects of the Citrus flavonoids in the prevention or treatment of ND. This review may be used as scientific basis for the development of nutraceuticals, food supplements or complementary and alternative drugs to maintain and improve the neurophysiological status.

Poor Folate Intake in a North Italian Pregnant Population: an Epidemiological Survey.

BACKGROUND: The association between folic acid (FA) insufficiency and congenital malformations has been demonstrated in over the past two decades. The aim of the present study was to investigate the use and timing of folate intake among a large sample of pregnant women in a north Italian region. METHODS: A multicentre prospective cohort study was conducted over a 14-month period in the maternity wards of five general hospitals (2301 women). Data were collected via a face-to-face interview. RESULTS: Seven hundred sixty women (33%) took at least one product containing FA. Seven hundred thirty-three (31.8%) women consumed multivitamins containing 413 (17.9%) consumed products containing FA only and 17 (0.7%) 15 mg of levofolinic acid. Only 0.9% of all women took FA before pregnancy 72.5% of women who consumed FA started during the first trimester. The most common dosage was 0.4 mg (19.4%). CONCLUSIONS: Very few women in the population are taking FA before pregnancy. Moreover, while most women consuming FA started in the first trimester, it is likely that they did so after closure of the neural tube. An important action is the recommendation that periconceptional supplementation programmes be promoted.

Clinical pharmacology of melatonin in the treatment of tinnitus: a review.

PURPOSE: We performed a review with the purpose to summarise, analyse and discuss the evidence provided by clinical studies evaluating effectiveness of melatonin in the cure of tinnitus. Due to the fact that there is no satisfactory treatment for tinnitus, clinical research has explored new therapeutic approaches. METHODS: A search of Pubmed, Medline, Embase, Central and Google Scholar was conducted to find trials published prior March 2014 on melatonin in the treatment of tinnitus. Design of the studies, randomization, allocation concealment procedures and diagnostic instruments (scales for tinnitus evaluation) were critical evaluated. RESULTS: Five clinical studies have been included. Three of them tested effectiveness of melatonin alone, the remaining two along with sulpiride and sulodexide respectively. Considered clinical trials adopted various experimental designs: single arm, randomised placebo-controlled and randomised placebo-controlled followed by crossover. These studies were characterised by several methodological weaknesses. CONCLUSION: Confirmation of melatonin clinical effectiveness in the treatment of tinnitus cannot be given in the light of the biases observed in the considered evidence. Melatonin seems to improve sleep disturbance linked to tinnitus.

Serenoa repens as an Endocrine Disruptor in a 10-Year-Old Young Girl: A New Case Report.

Serenoa repens, commonly known as saw palmetto, is the sole species currently classified in the genus Serenoa. The plant is a low shrubby palm that is native of West Indies, and it grows in the coastal lands of North America and other European mediterranean countries. Its fruits contain high concentrations of fatty acids and phytosterols. S. repens extracts have been studied for the symptomatic treatment of benign prostatic hyperplasia. Recently, they have been proposed to treat androgenic alopecia and other hair disorders. We report a new case of hot flashes in a 10-year-old girl using a food supplement containing the extract of S. repens for the treatment of hirsutism. When the girl discontinued the treatment, the hot flashes stopped. A 'rechallenge' of the supplement was tried and symptoms reappeared. About 4 months after starting therapy, the girl experienced menarche. Exposure to the plant-derived product could be responsible for the appearance of menarche. In our opinion, use of phytotherapeutic agents in pediatric patients should be associated to a better evaluation of benefit/risk profile taking in account the physiological changes that occurs at different ages in this subgroup of population.

Contact dermatitis as an adverse reaction to some topically used European herbal medicinal products - part 2: Echinacea purpurea-Lavandula angustifolia.

This review focuses on contact dermatitis as an adverse effect of a selection of topically used herbal medicinal products for which the European Medicines Agency has completed an evaluation up to the end of November 2013 and for which a Community herbal monograph has been produced. Part 2: Echinacea purpurea Moench-Lavandula angustifolia Mill.